 Pim kinases are emerging targets for cancer therapeutics.1 A number of research organizations are developing Pim inhibitors, and AZD-1208 and LGH447 are the two most advanced experimental drugs currently in phase-1 clinical trials for treatment of hematological and solid tumors.2 In this poster communication, we report our research efforts in the discovery of potent and bioavailable pan-Pim inhibitors for the treatment of Multiple Myeloma (MM). An X-ray co-crystal structure of an indazole screening hit 1  bound to Pim-1 kinase revealed the key binding interactions within the ATP binding site. Using compound 1  as a template, screening of analogous core fragments identified a 6-azaindazole moiety as a new core for further development. Structure- and fragment-based drug design led to identification of compound 2  as potent pan-Pim inhibitor with low picomolar biochemical potency on all three Pim kinase isoforms. To improve the bioavailability of compound 2  , compound 3 was discovered which has excellent potency, good oral bioavailability, and improved kinase selectivity. In this presentation, structural activity relationship, syntheses and co-crystal structures of this series will be described.References1. (a) Magnuson, N. S.; Wang, Z.; Ding, G.; Reeves, R. Future Oncol. 2010, 6, 1461-1478; (b) Merkel, A. L.; Meggers, E.; Ocker, M. Expert Opin. Investig. Drugs 2012, 21, 425.2. (a) http://clinicaltrials.gov/ct2/results?term=AZD-1208&Search=Search. (b) http://clinicaltrials.gov/ct2/results?term=LGH447&Search=Search.

Discovery of potent and bioavailable pan-Pim inhibitors for treatment of cancer

248th National Meeting (2014)

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